ABSTRACT Opioid use disorders (OUDs) are increasing at alarming rates in women. Stress and dysregulation in biologic stress response systems appear to play an important role in drug use, and the connection between stress and drug use may be particularly important for women. Alterations in the hypothalamic-pituitary-adrenal axis and noradrenergic system are important in pathophysiology of OUDs. There is evidence that alpha-2 adrenergic agonists, agents that decrease noradrenergic activity, may help to prevent relapse and decrease stress reactivity in individuals with OUD and prevent relapse to drug use. Of interest, alpha-2 adrenergic agents have demonstrated greater effect in decreasing stress-reactivity and craving in cocaine- and nicotine-dependent women as compared to men, but gender differences in the impact of alpha-2 adrenergic agents in individuals with OUD have not been systematically explored. In the proposed study, we will explore the impact of a new alpha-2 adrenergic agent, lofexidine, on stress and drug cues in a laboratory paradigm and on stress cues delivered in participants' natural environments over the course of a 4-week clinical trial in 208 opioid-dependent men and women (104 women, 104 men). We will use innovative mobile technology to measure response to stress cues repeatedly before, during, and after treatment to allow for assessment of craving, emotional state and stress-cue reactivity in the natural environment of women and men with OUD. We will also measure urine drug screens three times per week and assess medication compliance using an innovative video capture procedure. The proposed study has significant synergies with Projects 1 and 3, utilizing similar assessment and pharmacologic interventions, respectively. This project will provide important information about a novel treatment strategy which may expand personalized medicine strategies for individuals with OUD.